The Bay Area Breast Cancer SPORE renewal application focuses on unmet needs in two areas - improved management of premalignant disease and more effective treatment of invasive cancer subtypes that do not respond well to current therapeutic strategies and that are at high risk of metastasis. Our approach is based on the increasingly well-established concept that breast cancer is a heterogeneous disease in which molecularly defined subsets progress and respond differentially to therapy. Work proposed in this renewal application will be carried out in four projects: Project 1 - Risk Stratification for Subsequent Tumors in Women with DCIS will test the hypothesis that the molecular events discovered to be important in early breast cancer development during the last project period will be associated with risk of subsequent progression of DCIS to invasive cancer. Project 2 - Genomic Approaches to Breast Cancer Subsets Identification and Treatment will identify FDA approved and experimental drugs that are effective against basal and luminal/amplifier breast cancer subtypes, develop molecular marker assays to guide the clinical introduction of these drugs and explore the molecular mechanisms through which effective drugs operate. Project 3 - Nanoparticle-based Chemotherapy against Aggressive Breast Cancer Subtypes will develop lipidic nanoparticle-based therapies immunologically targeted to aggressive breast cancer phenotypes, with particular emphasis on treatment of basal-like tumors. Project 4 - Breast Cancer Therapeutic Agents Based on Telomerase Misfunction will continue to develop a nucleic acid construct to knock down expression of endogenous human telomerase RNA (siRNA against hTer) and introduce mutant-template hTer (MT-hTer) to force synthesis of mutant telomeres thereby inducing a rapid DMA damage response with telomere uncapping and apoptosis. These projects will supported by cores for Administration, Tissue and Outcomes, Biostatistics, Bioinformatics. In addition, an Advocacy Core infuses relevant patient experiences into the SPORE, addresses recurrent barriers to translational research, and networks with various organizations throughout the Bay Area and nationally.